Potassium channel blockers

ABSTRACT

The present invention provides a compound of formula (I) 
                         
or its salts or pharmaceutically acceptable derivatives thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , and j are defined herein. The compounds are useful as potassium ion channel inhibitors.

This application claims the benefit of U.S. Provisional Appl. No. 61/093,230. This application is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) which are potassium channel inhibitors. Compounds in this class may be useful as Kv1.3 inhibitors for immunomodulation and the treatment of autoimmune, chronic inflammatory, metabolic diseases and the like. Additionally, compounds in this class may also be useful as Kv1.5 inhibitors for the treatment or prevention of arrhythmias. Pharmaceutical compositions comprising the compounds and their use in the treatment of autoimmune and inflammatory diseases and in the treatment of arrhythmia are also provided.

BACKGROUND

Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na⁺, K⁺, Ca²⁺ and Cl⁻ can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see Gutman et al., 2003).

Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases (Shieh et al., 2000; Ford et al., 2002, Xie et al, 2004, Cahalan et al, 1997). The potassium channel Kv1.3 is found in a number of tissues including neurons, blood cells, osteoclasts, macrophages, epithelia, and T- and B-lymphocytes. Furthermore, Kv1.3 inhibition has been shown to modulate T-cell function which has implications in many autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, obesity, diabetes and inflammatory bowel disease (Beeton et al., 2006).

Kv1.3 Channel Blockers for Autoimmune Disorders

The role of autoreactive, late-stage, memory T-cells in the pathogenesis of a variety of autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, IBD and others is well established. Activation of T_(EM) cells is followed by substantial up-regulation of Kv1.3 channel expression and, as a result, Kv1.3 becomes the predominant route of potassium efflux from the cell. Thus, selective blockade of Kv1.3 causes membrane depolarisation and inhibition of Ca²⁺ influx, leading to inhibition of cytokine production and cell proliferation and function. Kv1.3 thus represents a novel therapeutic target of great interest for autoimmune disease control.

T-cells and Autoimmunity

T-cells are lymphocytes which play a central role in cell mediated immunity. One of the major forms of T-cell is the helper T-cell (T_(H)), also known as CD4+ cells which plays an essential role in the development of autoimmune diseases. Through the production of the cytokine interleukin 2 (IL-2), CD4+ T-cells can create the second main type of T-cell known as cytotoxic T-cells (CD8+). Naïve (inactive) CD4+ and CD8+ T-cells express both proteins (CCR7+CD45RA+) and use the chemokine receptor CCR7 as a key to gain entry into lymph nodes. Within lymph nodes, the naïve T-cells encounter antigen and through an activation process, change into “effector” T-cells that produce cytokines and proliferate. Once the ensuing immune response subsides, most naïve effectors die, but a few differentiate into long-lived central memory cells (T_(CM)). T_(CM) cells, like naïve cells, use CCR7 to home to the lymph nodes to encounter their cognate antigen. Upon antigenic stimulation, T_(CM) cells change into “T_(CM) effector” cells that produce cytokines and proliferate. They too suffer the same fate as naïve effectors, the majority dying after the immune response wanes, leaving a few long-lived survivors for further challenge. Repeated antigenic challenge, as might happen in autoimmune diseases or in chronic infections, causes T_(CM) cells to differentiate into short-lived “effector memory T-cells” (T_(EM)) that lack expression of both CCR7 and CD45RA, and do not need to home to lymph nodes for antigen-induced activation. A subset of CD8+ T_(EM) cells reacquire CD45RA and become CCR7−CD45RA+ T_(EMRA) cells. Upon activation, both CD4+ and CD8+ T_(EM) cells change into T_(EM) effectors that migrate rapidly to sites of inflammation and produce large amounts of the proinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosis factor α (TNFα). In addition, CD8+ T_(EM) effectors carry large amounts of perforin and are therefore immensely destructive (Wulff et al, 2003, Beeton et al, 2005).

Functional Role of Kv1.3 in T-cells and Autoimmune Disorders

Human T-cells express two K⁺ channels, Kv1.3 and IKCal, that provide the counterbalance cation efflux necessary for the sustained elevation of cytosolic Ca²⁺ levels required for gene transcription, proliferation and cytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The Kv1.3 and IKCal (also known as KCa3.1) channels regulate membrane potential and facilitate Ca²⁺ signalling in T-lymphocytes. Kv1.3 opens in response to membrane depolarisation and maintains the resting membrane potential (initiation phase), whereas IKCal opens in response to an increase in cytosolic Ca²⁺ and hyperpolarises the membrane potential (Beeton et al, 2001). Selective blockade of K⁺ channels leads to membrane depolarisation, which in turn inhibits Ca²⁺ influx and shuts down cytokine production and cell proliferation. Early in vitro studies, using channel blocker toxins, clearly demonstrate that Kv1.3 channels are essential for the synthesis (gene activation) and secretion of the cytokine IL-2 after T-cell activation (Price et al, 1989) and provide a rationale for the potential therapeutic use of inhibitors of this channel in immunological disorders. The role of autoreactive T-cells in the pathogenesis of autoimmune diseases has clearly been demonstrated in animal models. Disease-specific, autoreactive T-cells in several other autoimmune diseases are also reported to exhibit a memory phenotype. Autoreactive T_(EM) cells are also implicated in psoriasis, rheumatoid arthritis, multiple sclerosis, IBD, vitiligo, uveitis, pemphigus, inflammatory myopathies, Hashimito disease, and scleroderma (Beeton et al, 2005). “Late” memory T- and B-cells have been implicated in the disease progression and tissue damage in a number of autoimmune diseases, in transplant rejection and chronic graft-versus-host disease. Modulators of the Kv1.3 channel may allow selective targeting of disease-inducing effector memory T-cells and memory B-cells without compromising the normal immune response and as a result are likely to have a preferred side-affect profile than agents that bring about more general immunosuppression.

The observation that the Kv1.3 blocker margatoxin (MgTX) effectively suppressed the delayed-type hypersensitivity (DTH) response in vivo was provided by Koo et al, 1999. In addition MgTX was also shown to inhibit primary antibody response in non-sensitised animals (secondary antibody response was not affected by MgTX. These latter results are in agreement with the notion that Kv1.3 channels are predominant in resting T lymphocytes and regulate their function, while IKCal channels are more important in pre-activated T lymphocytes. Correolide (Koo et al, 1999) and PAP-1 (Schmitz et al, 2005) are novel immunosuppressants which block Kv1.3 channels and are effective in the DTH model. Because the cellular components involved in DTH response are similar to those found in autoimmune diseases and allograft rejection, the results obtained are very promising for the development of Kv1.3 channel blockers as new immunosuppressants.

In the early 1980's a number of compounds were reported to block Kv1.3 channels at micromolar to millimolar concentrations as described by Triggle et al, in “Voltage Gated Ion Channels as Drug Targets” these include classical Kv channel inhibitors such as 4-aminopyridine and tetramethylammonium, and other non specific compounds such as the calcium activated potassium channel blockers quinine and ceteidil, the phenothiazine antipsychotics chloropromazine and trifluoroperazine, the classical calcium channel inhibitors verapamil, diltiazem, nifedipine and nitrendipine, and the beta blocker propranolol.

Also in the 1980's natural products extracted from scorpions, snakes and other marine organisms were found to be potent inhibitors of Kv1.3 channels, these were primarily short peptides (<70 residues) that are stabilised by multiple sulphide bonds. The first of these potent inhibitors was isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands et al, 1989), there after screening of other scorpion venoms led to the identification of more potent Kv1.3 blocking toxins, these include margatoxin (MgTX) (Garcia et al, 1993), agitoxin-2 (Garcia et al, 1994), hongotoxin (Koshchak et al, 1998), pandinus imperator toxin 2 (Pi2) (Peter et al, 2001) and orthochirus scrobiculosus (OSK1) (Mouhat et al, 2005) among others. With the exception of OSK1 (300 fold selective over the nearest related channel) none of the scorpion toxins were selective for Kv1.3

One of the most potent and selective Kv1.3 blockers to date, which was extracted from sea anemone is stichodactyla helianthus toxin (Shk) (Pennington et al, 1996) this has been reported for the treatment of autoimmune disease through the blockade of Kv1.3 (U.S. Pat. No. 6,077,680). Shk and its synthetic derivative Shk-Dap²² with improved selectivity profile display pico molar activity (Pennington et al, 1998) however, these peptides proved to have unfavourable properties for further development.

Recently more novel and selective small molecule Kv1.3 channel blockers have been reported for the management of autoimmune disorders. These include the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al., 1996), the benzhydryl piperidine UK-78,282 (Hanson et al. 1999), correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC (U.S. Pat. No. 6,194,458, WO0025774), sulfamidebenzamidoindane (U.S. Pat. No. 6,083,986), Khellinone (Baell et al., 2004), dichloropenylpyrazolopyrimidine (WO-00140231) psoralens (Wulff et al., 1998, Vennekamp et al., 2004, Schmitz et al., 2005) and isoindolines (WO 2008/038051).

Furthermore, the related Kv1.5 channel is expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review of Brendel and Peukert, 2002): (i) There is evidence that Kv1.5 underlies the cardiac ultrarapid delayed rectifier (Kv_((ur))) physiological current in humans due to similar biophysical and pharmacological properties (Wang et al., 1993; and Fedida et al., 1993). This has been supported with antisense oligonucleotides to Kv1.5 which have been shown to reduce Kv_((ur)) amplitude in human atrial myocytes (Feng et al., 1997). (ii) electrophysiological recordings have demonstrated that Kv_((ur)) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation (Amos et al., 1996; Li et al., 1996; and Nattel, 2002). (iii) Inhibiting Kv_((ur)) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes (Courtemanche et al., 1999). (iv) Prolonging the action potential duration by selectively inhibiting Kv1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered (Nattel et al., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias (Colatsky et al., 1990).

Drugs that maintain the sinus rhythm long-term without proarrhythmic or other side effects are highly desirable and not currently available. Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating Kv1.5 or Kv_((ur)). The known class III antiarrythmics ambasilide (Feng et al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al., 1995) and bertosamil (Godreau et al., 2002) have all been reported as potassium channel blockers of Kv_((ur)) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models (Matsuda et al., 2001), and S9947 inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and Kv_((ur)) in native rat and human cardiac myocytes (Bachmann et al., 2001). Elsewhere, other novel potassium channel modulators which target Kv1.5 or Kv_((ur)) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189) anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloalkylamine derivatives (WO2005018635), isoquionolines (WO2005030791), quinolines (WO2005030792), imidazopyrazines (WO205034837), benzopyranols (WO2005037780), isoquinolinones (WO2005046578), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155 WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475 WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).

Sulphonamides have been reported to be useful as inhibitors of 11-beta-hydroxysteroid dehydrogenase type1, CCR5, H3 receptor and mitotic kinesins amongst others.

Substituted aryl tertiary sulphonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of 11-betehydroxysteroid dehydrogenase type1, for the treatment and prevention of hyperglycemia in diseases such as type-2 diabetes (WO2004065351).

Substituted aryl tertiary sulphonamides, wherein position 3 is optionally substituted with substituted alky, alkoxyamino, sulfonyl, acyl, alkoxy carbonyl or aminocarbonyl have been claimed as inhibitors of mitotic kinesins as effective anti cancer agents (WO2007056078).

Substituted 1-3 phenyl sulphonamides bearing a benzyl group and an amido group have been claimed as useful for the treatment and/or prophylaxis of viral diseases, in particular for the treatment of Hepatitis C (WO 2007/110171)

Elsewhere, arylsulophonylaminobenzene derivatives bearing an alkylamino group meta to the sulphonamide were found to be inhibitors of Factor Xa and useful in the treatment of arterial and venous thrombotic occlusive disorders, inflammation, cancer and neurodegenerative diseases (WO 96/40100).

Substituted 1,3 phenylsulphonamides containing an amido group meta to the sulphonamide have been claimed as inhibitors of BACE as an effective means for treating and preventing Alzheimer's and related diseases caused by the production of beta-amyloid (WO 2005/030709).

Substituted 1,3 phenylsulphonamides containing an ether group meta to the sulphonamide have also been claimed as liver X receptor (LXR) modulators useful for the treatment or prevention of diseases associated with the activity of LXR's (WO2003082205)

Substituted 1,3 phenylsulphonamides containing an alkylamino group meta to the sulphonamide have been claimed as amidino protease inhibitors useful for the treatment of protease mediated diseases such as thrombosis, ischemia, or inflammation (WO 1998/01422).

Substituted 1,3 phenylsulphonamides have been claimed as cell proliferation modulators through inhibition of microtubule formation which could be useful for the treatment of cancer related disease (WO00/73264).

Additionally, substituted 1-3 phenylsulphonamides with a substituted amino group meta to the sulphonamide have been claimed as urotensin-II receptor antagonists and CCR-9 antagonists useful for the treatment of gastric diseases, arthritis, osteoperosis and urinary incontinence (WO2004/73634).

It has now surprisingly been found that compounds of general formula (I) set out below act as inhibitors of potassium channels. These compounds are particularly useful for inhibiting the potassium channel Kv1.3 and treating diseases associated with the inhibition of the potassium channel Kv1.3. This invention is not limited to treating diseases mediated by Kv1.3, the compounds also being useful to treat diseases which require Kv1.5 potassium channel inhibition for example atrial fibrillation (Marban, 2002, Brendel and Peukert, 2002).

Thus, in a first aspect, the present invention provides a compound of formula (I)

or its salts or pharmaceutically acceptable derivatives thereof wherein; X₁ is selected from a group consisting of CH, O or N; R₁ is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; R₂ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl or NR₆R₇; R₃ is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulphonyl or nitrile; R₄ is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl R₅ may be hydrogen or may, together with R₄ and X₁ (when X₁=N), form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II)

Wherein; X₂ is C(═O), CH₂, CH(R_(8a)) or C(R_(8a))(R_(8b)); X₃ is CH₂, CH(R_(9a)), C(R_(9a))(R_(9b)), NH, N(R_(9c)), O or S; R₆ and R₇ are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; R_(8a) and R_(8b) for each occurrence is independently halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; R_(9a) and R_(9b) for each occurrence is independently halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; R_(9c) is optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; With the proviso that: When X₁ is O then j=0 When X₁ is N or CH then j=1 n=1, 2 or 3

In one embodiment of the invention a compound of the following formula is provided:

or its salts or pharmaceutically acceptable derivatives thereof wherein; X₁ is selected from a group consisting of CH, O or N; R₁ is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; R₂ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl or NR₆R₇; R₃ is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulphonyl or nitrile; R₄ is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl R₅ may be hydrogen or may, together with R₄ and X₁ (when X₁=N), form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II)

Wherein; X₂ is C(═O), C(R₈)₂; X₃ is, C(R₉)₂, N(R_(9b)), O or S; R₆ and R₇ are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; R₈ for each occurrence is independently hydrogen, halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; R₉ for each occurrence is independently hydrogen, halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxyl, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; R_(9b) is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; With the proviso that: When X₁ is O then j=0 When X₁ is N or CH then j=1 n=1, 2 or 3

As used herein, the following definitions shall apply unless otherwise indicated.

The term “optionally substituted” means that a group may be substituted by one or more substituents which may be the same or different. When otherwise not specified, these substituents are selected from alkyl, cycloalkyl, —O—C(halogen)₃ preferably —OCF₃, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulphamoyl, sulphonyl, sulphinyl, sulphenyl, sulphonamido or urea.

The term “alkyl group” as used herein, is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, preferably 2, 3, 4, or 5 carbon atoms such as a C₁₋₄ alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one two or three substituents. Suitable substituents include cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulphonamido, nitro, aryl and heteroaryl. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety. An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond. An “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.

The term “cycloalkyl” as used herein refers to mono- or bicyclic ring or ring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms. The ring system may be a “saturated ring”, which means that the ring does not contain any alkene or alkyne moieties. The cycloalkyl group may also be an “unsaturated ring” which means that it contains at least one alkene or alkyne moiety and the ring system is not aromatic. The cycloalkyl group may be unsubstituted or substituted as defined herein. In addition to the above mentioned substituents one or more ring carbon atoms may also be bonded via a double bond to a group selected from NH, S and O. The cycloalkyl substituent may be bonded via a linker group such as a C₁₋₆ alkyl group, except where the optional substituent is alkyl. One or more hydrogens of the alkyl group in the linker may be replaced by a moiety selected from the group consisting of hydroxy, halo, cyano, amino, thiol, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylamino and C₁₋₆dialkylamino.

The term “aryl group” as used herein, is typically a C₆₋₁₀ aryl group such as phenyl or naphthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido, NN-dialkylamino, sulphonamido, aryl and heteroaryl.

The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures and the atoms forming the backbone of the ring(s) are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings. Carbocyclic groups include both, a “cycloalkyl group”, which means a non-aromatic carbocycle, and a “carbocyclic aryl” group, which means an aromatic carbocycle. The carbocyclic group may optionally be substituted as defined herein.

The term “heterocyclic” or “heterocyclo” as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 1 to 6 carbon atoms in addition to the heteroatom(s). The term heterocyclic group include both a “heteroalicyclic” group, which means a non-aromatic heterocycle and a “heteroaryl” group, which means an aromatic heterocycle. The heterocyclic moiety may be unsubstituted or substituted as defined herein and the substituents, when positioned adjacent to one another, may combine to form cycloalkyl or heteroalicyclic ring systems for example methylendioxy or difluoromethylendioxy. The heterocyclic substituent may be bonded via a carbon atom or a heteroatom. The heterocyclic group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur are present in the ring.

The term “heteroaryl” as used herein refers to mono- or bicyclic ring or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 1 to 13 carbon atoms in addition to the heteroatom(s) and contain at least one aromatic ring with a heteroatom. The heteroaryl group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur is present. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heterocycles include but are not limited to indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl and the like. Examples of tricyclic heterocycles include but are not limited to thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. The heteroaryl group may be unsubstituted or substituted as defined herein. The substituents, when positioned adjacent to one another, may combine to form a cycloalkyl or heteroalicyclic ring for example methylendioxy and difluoromethylendioxy. The heteroaryl substituent may be bonded via a carbon atom or a heteroatom.

The term “arylalkyl”, as used herein, refers to a chemical moiety of formula aryl-C₁₋₆alkyl or C₁₋₆alkyl-aryl as those terms are defined herein.

The term “heteroarylalkyl”, used as herein, refers to a chemical moiety of formula heteroaryl-C₁₋₆alkyl or C₁₋₆alkyl-heteroaryl as those terms are defined herein.

The term “acyl”, as used herein, refers to a chemical moiety of formula (CH₂)yC(═O)Rz wherein y is 1-6

The term “amidino” refers to a chemical moiety with the formula (CH₂)yC(═NH)NRzR′z wherein y is 1-6.

The term “amido” refers to both, a “C-amido” group which means a chemical moiety with the formula —C(═O)NRzR′z and a “N-amido” group which means a chemical moiety with the formula —NRzC(═O)R′z.

The term “amine” or “amino” refers to a chemical moiety of formula —NRzR′z. The definition of an amine is also understood to include their N-oxides.

A “cyano” group refers to a chemical moiety of formula —CN.

The term “hydroxy” or “hydroxyl” as used herein, refers to a chemical moiety of formula —OH.

The term “halogen” or “halo” refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

The term “alkanoyl”, as used herein, refers to a chemical moiety with the formula —C(═O)Rz.

The term “sulfone” or “sulfonyl” refers to a chemical moiety with the formula —S(═O)₂Rz.

The term “sulfinyl” refers to a chemical moiety with the formula —S(═O)Rz.

The term “sulfenyl” refers to a chemical moiety with the formula —SRz.

A “sulfamoyl” group refers to a chemical moiety with the formula —NRz—S(═O)₂NRzR′z.

The term “sulfonamido” refers to both an “S-sulfonamido” group which means a chemical moiety with the formula —S(═O)₂NRzR′ z and an “N-sulfonamido” group which means a chemical moiety with the formula —N—S(═O)₂R′z.

The term “thiocarbonyl” refers to a chemical moiety with the formula (CH₂)yC(═S)Rz wherein y is 1-6.

The term “thio” or “thiol”, as used herein, refers to a chemical moiety of formula —SH.

The term “thioamide” refers to both a “C-thioamido” group which means a chemical moiety with the formula (CH₂)yC(═S)NRzR′z and a “N-thioamido” group which means a chemical moiety with the formula (CH₂)yNRzC(═S)R′z wherein y is 1-6.

An “urea” group refers to a chemical moiety of formula —NRzC(═O)NRzR′z.

Rz and R′z are independently selected from the group consisting of hydrogen, C₁₋₆alkyl, cycloalkyl, C₁₋₆alkoxy, aryl-C₁₋₆alkyl, aryl and heteroaryl.

One preferred embodiment relates to compounds where R₂ is;

NR₆R₇ or a compound of formula (III), (IV) (V) or (VI)

Wherein; R₆ and R₇ are the same or different and each represents hydrogen, or optionally substituted C₁₋₃ alkyl; A, Q, T, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of A, Q, T, D, or E is N; Where R₂ is selected from compounds of formula (III), E may also represent O or S and Where R₂ is selected from compounds of formula (IV), A may also represent O or S; R₁₁ and R₁₂ are the same or different and each represents hydrogen, halogen, hydroxyl, nitrile, optionally substituted amino, optionally substituted acyl, optionally substituted C₁₋₃ alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring. Preferably, R₁₁ and R₁₂ are alkyl, preferably CH₃; R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkyl, any of the pairs R₁₃ and R₁₄, or R₁₄ and R₁₅, or R₁₅ and R₁₆, or R₁₆ and R₁₇ or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring R₁ is selected from compounds of Formula (VII)

Wherein; R₁₈, R₁₉, R₂₀, R₂₁ and R₂₂ are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkyl or optionally substituted alkoxy. Preferably R₁₉, R₂₀ and R₂₁ are the same or different and each represents H, Cl, F, or CH₃ most preferably Cl. R₂₃ and R₂₄ are the same or different and each represents hydrogen, hydroxyl, and optionally substituted C₁₋₃ alkyl. R₃ is H, F or CH₃, Where X₁ is O or N:— R₄ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, substituted benzyl, substituted phenethyl, 3-phenylpropyl, methylpyridine, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide. Where X₁ is N, R₅ is preferably taken together with X₁ and R₄ to from an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II) as defined above. Preferred compounds are those of formula (VIII);

Wherein X₁ is selected from N or O; R₂ is NR₆R₇, substituted imidazole, substituted pyrazole, substituted pyrrole, substituted oxazole, substituted oxadiazole, substituted thiazole, substituted thiadiazole, substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted triazine, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, aminophenyl, acetamidophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzooxadiazole, substituted benzodioxole, substituted indoline, substituted indole, substituted indazole or substituted benzomorpholine. R₆ and R₇ are methyl R₃, R₄, R₅, R₁₈, R₁₉, R₂₀, R₂₁ and R₂₂ are as defined above.

More preferred are compounds of formula (IX);

Wherein; X₁ is selected from N or O; R₂ is NR₆R₇, substituted imidazole, substituted pyrazole, substituted pyridine, phenyl, fluorophenyl, cyanophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzooxadiazole, substituted benzodioxole, substituted indoline, or substituted benzomorpholine; R₃ is H, or F; When X₁ is N or O; R₄ is methylpyridine, substituted hydroxyethyl, hydroxypropyl, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide; When X₁ is N; X₁, R₄ and R₅ together form substituted piperidine, substituted morpholine, substituted piperazine, substituted pyrrolidine, and substituted imidazolidin-2-one; R₆, R₇, R₁₉, R₂₀ and R₂₁ are as defined above. Particularly preferred compounds of the invention include:

-   N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-acetamide -   3-Methyl-3H-imidazole-4-carboxylic acid     [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide -   1-Methyl-1H-imidazole-4-carboxylic acid     [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide -   N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-phenyl-acetamide -   N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-methoxy-acetamide -   1-Methyl-1H-imidazole-4-sulfonic acid     benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide -   N-Benzyl-N-[3-(3-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide -   N-Benzyl-N-[3-(4-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide -   N-Benzyl-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide -   Pyridine-3-sulfonic acid     benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide -   3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid     benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid     benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1,2-Dimethyl-1H-imidazole-4-sulfonic acid     benzyl-(3-morpholin-4-yl-phenyl)-amide -   N-Benzyl-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide -   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid     benzyl-(3-morpholin-4-yl-phenyl)-amide -   N-Benzyl-3-cyano-N-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzenesulfonamide -   N-Benzyl-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide -   1-Methyl-1H-pyrazole-4-sulfonic acid     benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1,2-Dimethyl-1H-imidazole-4-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   2-Methyl-2H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-4-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   N-(4-Chloro-benzyl)-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide -   2-Methyl-2H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   1-Methyl-1H-pyrazole-4-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   Pyridine-3-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   1-Methyl-1H-imidazole-4-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-[4-fluoro-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     benzyl-(3-morpholin-4-yl-phenyl)-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-3-sulfonic acid     benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide -   N-Benzyl-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide -   2-Methyl-2H-pyrazole-3-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide -   1-Methyl-1H-pyrazole-4-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide -   N-(4-Chloro-benzyl)-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide -   N-(4-Chloro-benzyl)-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide -   Pyridine-3-sulfonic acid     benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-a(2-oxo-imidazolidin-1-yl)-phenyl]-amide -   Pyridine-3-sulfonic acid     (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-ylbenzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, araalkyl amines or heterocyclic amines.

The compounds of the invention can contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereo isomers of the compounds shown, including racemic and non racemic mixtures and pure enantiomers and/or diastereoisomers.

As discussed herein, the compounds of the invention are useful in the treatment of various conditions. Thus, in a second aspect, the present invention provides a compound of formula (I) as defined herein for use in medicine. Preferably the compound is used to prevent or treat conditions which require inhibition of potassium channels, such as immunological disorders, including psoriasis, rheumatoid arthritis and multiple sclerosis.

A further aspect the present invention provides a pharmaceutical formulation comprising at least one compound of formula (I) or as defined herein and optionally one or more excipients, carriers or diluents.

The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100 mg/day of the compound, preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/day or 60-100 mg/day. For compounds of formula I, doses in the range 100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600 mg/day or 500-1000 mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The compositions of the invention can be used to treat conditions which require inhibition of potassium channels, for example in the treatment of immunological disorders. Thus, in further aspects, the present invention provides:

(i) A method of treating or preventing a disorder which requires potassium channel inhibition, eg immunological disorders comprising administering to a subject an effective amount of at least one compound of the invention or a pharmaceutical composition of the invention and (ii) the use of a compound of the invention in the manufacture of a medicament for use in potassium channel inhibition.

In particular, the medicament is for use in the treatment or prevention of psoriasis, rheumatoid arthritis, multiple sclerosis and other immunological disorders and arrhythmia.

Preferred embodiments of the first aspect apply to all other aspects mutatis mutandis.

The compounds of formula (I) may be prepared by conventional routes, for example those set out in Schemes 1 to 6 shown below.

Compounds of formula (I) where X₁ is N and R₄ and R₅ are described as in claim 1, may be synthesised by reaction of an amine of formula NR₄R₅ with an aromatic halide of formula (X) where G is Cl, Br, I or F as shown in Scheme 1. This substitution may be carried out thermally, optionally with microwave heating and optionally in the presence of solvent. Alternatively, the substitution may be carried out via an organometallic mediated coupling between an amine of formula NR₄R₅ with an aromatic halide of formula (X). Suitable conditions include those developed by Buchwald et al¹. The Buchwald coupling may be carried-out using a palladium-organophosphine complex, such as that derived from palladium acetate and dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in solvent such as dioxane, and in the presence of a base such as sodium tert-butoxide. The reaction may be carried out at room temperature or optionally with heating or optionally with microwave heating.

Compounds of formula (X) may be prepared from compounds of formula (XI) and sulphonyl chlorides of formula R₂SO₂Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R₂SO₂Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (XI) may be prepared from compounds of formula (XII) via reductive amination of a ketone or aldehyde of formula R₁(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XII) are either commercially available or may be prepared by standard published methods familiar to those skilled in the art.

Compounds of formula (I) where X₁ is N, R₅ is H and R₄ is optionally substituted acyl may be synthesised by reaction of compounds of formula (XIII) and compounds of formula R_(z)COA where A is OH, Cl or Br as shown in Scheme 2. Where A is OH, the reaction may be carried out in the presence of a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at range of temperatures from ambient to reflux temperature or optionally with microwave heating. Where A is Cl or Br the reaction may be carried out in the presence of base such as pyridine, or diisopropylamine and in the presence of solvent such as dichloromethane or tetrahydrofuran, optionally at room temperature or optionally with heating or optionally with microwave heating. Compounds of formula R_(z)COA are either commercially available or may be prepared by standard published methods familiar to those skilled in the art.

Compounds of formula (I) where X₁ is N, R₅ is H and R₄ is optionally substituted sulfonyl may be synthesised by reaction of compounds of formula (XIII) and compounds of formula R_(Z)SO₂Cl. The reaction may be carried out in the presence of base such as pyridine, or diisopropylamine and in the presence of solvent such as dichloromethane or tetrahydrofuran, optionally at room temperature or optionally with heating or optionally with microwave heating.

Compounds of formula (XIII) may be prepared from compounds of formula (XIV) by removal of a protecting group (P) in a preferred instance a tertbutylcarboxy (BOC) group. This may be done using standard methods of acidic or basic hydrolysis or via protolytic decomposition such as trifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XIV) may be prepared from compounds of formula (XV) and sulphonyl chlorides of formula R₂SO₂Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R₂SO₂Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (XV) may be prepared from compounds of formula (XVI) via reductive amination of a ketone or aldehyde of formula R₁(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XVI) are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Alternatively, compounds of formula (I) where X₁ is N and R₄ and R₅ are described as in claim 1, may be prepared from compounds of formula (XVII) and sulphonyl chlorides of formula R₂SO₂Cl as shown in Scheme 3. Typically, the reaction is performed in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R₂SO₂Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (XVII) may be prepared from compounds of formula (XVIII) via reductive amination of a ketone or aldehyde of formula R₁(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. Reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as Sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XVIII) where R₅ is H are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (XVIII) where R₄ and R₅ are taken together to form an optionally substituted saturated or partially saturated 5 membered ring may be synthesized from compounds of formula (XIX) via reduction of a nitro group as shown in Scheme 4. This reduction may be accomplished via a suitable reducing agent such as Tin (II) chloride in the presence of hydrochloric acid or via catalytic hydrogenation using a suitable catalyst such as palladium on carbon which may be carried out at atmospheric or elevated pressure and optionally with microwave heating and optionally in the presence of a hydrogen equivalent such as ammonium formate.

Compounds of formula (XIX) may be prepared via cyclisation of compounds of formula (XX) where Q1 is CH₂Cl, CH₂Br, CO₂H or C(O)Cl. This cyclisation may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating.

Compounds of formula (XX) may be synthesized via reaction of compounds of formula (XXI) and compounds of formula (XXII) where Q2 is CO₂H, C(O)Cl, CH₂Cl, or CH₂Br, or X₂ and Q2 taken together are an isocyanate group.

Compounds of formula (XXI) and (XXII) are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Alternatively, compounds of formula (XVII) where R₄ and R₅ are taken together to form an optionally substituted saturated or partially saturated 5 membered ring may be prepared from compounds of formula (XXIII) by removal of a protecting group (P) as shown in Scheme 5. In a preferred instance a tertiarybutylcarboxy (BOC) group is used. This may be done using standard methods of acidic or basic hydrolysis or via protolytic decomposition such as trifluoroacetic acid in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XXIII) may be prepared via cyclisation of compounds of formula (XXIV) where Q1 is CO₂H, C(O)Cl, CH₂Cl, or CH₂Br. This cyclisation may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating.

Compounds of formula (XXIV) may be synthesized via reaction of compounds of formula (XXII) and compounds of formula (XXV) where Q2 is CO₂H, C(O)Cl, CH₂Cl, or CH₂Br, or X2 and Q2 taken together are an isocyanate group. This reaction may be accomplished in the presence of base such as pyridine or sodium hydride and in the presence of solvent such as dichloromethane or tetrahydrofuran. The cyclisation may be carried out at room temperature or optionally with heating or optionally with microwave heating. Compounds of formula (XXII) or (XXV) are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (I) where X₁ is O and R₁, R₂ and R₄ are as described in the claims may be prepared from phenols of formula (XXVI) and compounds of formula R₄Br by standard methods such as alkylation as shown in Scheme 6. Typically this reaction is performed in the presence of a base for example potassium carbonate utilising standard methods familiar to those skilled in the art such as reaction in solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) where X₁ is O and R₄ are described in the claims may be prepared from phenols of formula (XXVI) and compounds of formula R₄OH by standard methods such as alkylation for example; Mitsunobu coupling (Mitsunobu 1981). The Mitsunobu coupling may be carried-out using diisopropyl azodicarboxylate (DIAD) or other appropriate coupling agents in the presence of triphenylphosphine. Typically, the reaction may be carried out at room temperature or optionally with heating or optionally with microwave heating in a suitable solvent for example tetrahydrofuran, acetonitrile or dichloromethane.

Compounds of formula (XXVI) may be prepared from compounds of formula (XXVII) and sulphonyl chlorides of formula R₂SO₂Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Compounds of formula R₂SO₂Cl are either commercially available or may be prepared by standard published methods known to those skilled in the art.

Compounds of formula (XXVII) may be prepared by de-protection of phenols with the general formula (XXVIII) where P is a protecting group, for example methyl. Typically, the de-methylation is carried out using halo borides for example Boron tribromide in a suitable solvent such as dichloromethane, tetrahydrofuran at temperatures ranging from 0° C. to reflux.

Compounds of formula (XXVIII) may be prepared from compounds of formula (XXIX) via reductive amination of a ketone or aldehyde of formula R₁(═O). The reaction may be performed in a one pot procedure with in situ formation and reduction of the imine or via a two stage process where the imine is isolated and purified prior to reduction. Imine formation is performed under acid catalysis, suitable catalysts include acetic acid. The reduction may be performed using standard methods such as reaction in solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature with a suitable reductant such as sodium triacetoxyborohydride or sodium cyanoborohydride, the reduction may also be performed using catalytic hydrogenation. Compounds of formula (XXIX) are either commercially available or may be prepared by standard published methods known to those skilled in the art.

The compounds of the invention are found to be inhibitors of potassium channels (K_(v)) and are therefore therapeutically useful. Such compounds are believed to be novel and the present invention also provides for these compounds. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds.

Many of the starting materials referred to in the reactions described above are available from commercial sources or can be made by methods cited in the literature references.

EXAMPLES

The HPLC analysis was conducted using the following methods:

Solvent: [MeCN-0.05% HCO₂H:H₂O-0.1% HCO₂H], 10-95% gradient 3 min, 95% 2.5 min; Column: Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase; Flow rate: 0.75 mL/min unless otherwise indicated.

Solvent: [MeCN-0.05% HCO₂H:H₂O-0.01% HCO₂H], 5-95% gradient 5 min, 95% 3 min; Column: Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase; Flow rate: 1.5 mL/min unless otherwise indicated.

Solvent: [MeCN:H₂O-0.1% HCO₂H], 5-95% gradient 3.5 min, 95% 2 min; Column: Phenomenex Gemini 50×3 mm i.d., C18 reverse phase; Flow rate: 1 mL/min unless otherwise indicated.

Solvent: [MeCN-0.05% HCO₂H:H₂O-0.1% HCO₂H], 5-95% gradient 6 min, 95% 3 min; Column: Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase; Flow rate: 1 mL/min unless otherwise indicated.

Preparative HPLC purification was conducted in the following manner: Solvent: [MeCN-0.05% HCO₂H:H₂O-0.1% HCO₂H], 5-95% gradient 12 min, 95% 3 min; Waters X-Bridge 100×19 mm i.d., C18 reverse phase; Flow rate: 16 mL/min unless otherwise indicated.

Example 1 N-Benzyl-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide (Method A) i) {3-[3-(2-Chloro-ethyl)-ureido]-phenyl}-carbamic acid tert-butyl ester

A solution of (3-Amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.4 mmol) and 1-Chloro-2-isocyanato-ethane (0.25 ml, 2.9 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). Combined organics dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by column chromatography (eluent 10% ethylacetate in dichloromethane) to afford the title compound (1 g). HPLC retention time 7.45 min. Mass spectrum (ES+) m/z 314 (M+H)

ii) [3-(2-Oxo-imidazolidin-1-yl)-phenyl]-carbamic acid tert-butyl ester

A solution of {3-[3-(2-chloro-ethyl)-ureido]-phenyl}-carbamic acid tert-butyl ester (1 g, 3.2 mmol) and potassium carbonate (1.32 g, 9.6 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. No reaction was observed. Sodium hydride (260 mg, 6.5 mmol, 60% dispersion in oil) was then added and reaction stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7.0 min. Mass spectrum (ES+) m/z 295 (M+NH₄)

iii) 1-(3-Amino-phenyl)-imidazolidin-2-one

A solution of [3-(2-oxo-imidazolidin-1-yl)-phenyl]-carbamic acid tert-butyl ester (0.88 g, 3.2 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (10 ml) were stirred at room temperature for 5 hours. The reaction was quenched with sodium carbonate (20 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo (0.54 g, 96%). HPLC retention time 1 min. Mass spectrum (ES+) m/z 178 (M+H).

The following compounds were synthesised according to this method using the appropriate starting materials;

-   N-(3-Amino-phenyl)-N-benzyl-benzene sulfonamide

iv) 1-(3-Benzylamino-phenyl)-imidazolidin-2-one

A solution of 1-(3-amino-phenyl)-imidazolidin-2-one (0.27 g, 1.5 mmol), benzaldehyde (0.17 ml, 1.7 mmol) and acetic acid (0.13 ml, 2.2 mmol) in dry tetrahydrofuran (10 ml) was stirred at room temperature for 6 hrs. Sodium borohydride (0.14 g, 3.8 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (25 ml) then extracted with dichloromethane (3×50 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7 min. Mass spectrum (ES+) m/z 268 (M+H).

The following compounds were synthesized according to this method using the appropriate starting materials

-   1-[3-(4-Chloro-benzylamino)-phenyl]-imidazolidin-2-one -   (4-Chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amine -   (4-Benzyl)-(3-morpholin-4-yl-phenyl)-amine -   1-[3-(4-Chloro-benzylamino)-phenyl]-pyrrolidin-2-one -   1-[5-(4-Chloro-benzylamino)-2-fluoro-phenyl]-pyrrolidin-2-one -   (3-Benzylamino-phenyl)-carbamic acid tert-butyl ester

v) N-Benzyl-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide (1)

A solution of 1-(3-benzylamino-phenyl)-imidazolidin-2-one (25 mg, 0.1 mmol), benzenesulphonyl chloride (39 μl, 31 mmol) and pyridine (27 μl, 34 mmol) in dry dichloromethane (1 ml) was heated to reflux for 15 hrs. The reaction mixture was then cooled to room temperature, quenched with water (10 ml) and extracted with dichloromethane (3×7 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by preparative TLC (eluent 1:1 ethyl acetate:dichloromethane) to afford the title compound as a off white solid (9 mg, 24%). HPLC retention time 8.8 mins. Mass spectrum (ES+) m/z 425 (M+NH₄).

Other compounds prepared by Method A as described for Example 1 using the appropriate starting materials are listed in TABLE 1

Example 2 N-Benzyl-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide (Method B) i) Benzyl-(3-bromo-phenyl)-amine

A solution of 3-bromo aniline (5 g, 29 mmol), benzaldehyde (3.24 ml, 32 mmol) and acetic acid (2.49 ml, 44 mmol) in dry tetrahydrofuran (50 ml) was stirred at room temperature for 3 hrs. Sodium borohydride (2.755 g, 73 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (100 ml) and extracted with dichloromethane (3×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 263 (M+H)

ii) N-Benzyl-N-(3-bromo-phenyl)-benzene sulfonamide

A solution of benzyl-(3-bromo-phenyl)-amine (2 g, 7.6 mmol), benzenesulphonyl chloride (3.2 ml, 25 mmol) and pyridine (2.2 ml, 27.5 mmol) in dry dichloromethane (50 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (3×75 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The crude residue was then purified by column chromatography eluting with dichloromethane to afford the title compound as a white solid (1.45 g, 47%). HPLC retention time 4.93 mins. Mass spectrum (ES+) m/z 402 (M+H).

iii) N-Benzyl-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide (2)

A solution of N-benzyl-N-(3-bromo-phenyl)-benzene sulfonamide (25 mg, 0.06 mmol), morpholine (6.5 μl, 0.07 mmol), palladium acetate (1 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2 mg) and sodium tert-butoxide (21 mg, 0.22 mmol) in dioxane (1 ml) were heated to 100° C. in the microwave for 30 minutes. The reaction was filtered, diluted with water (5 ml) and extracted with dichloromethane (3×6 ml). The combined organics were filtered, concentrated in vacuo and the residues purified by preparative TLC (eluent dichloromethane) to afford the title compound as a yellow solid (18 mg, 71%) HPLC retention time 8.3 min. Mass spectrum (ES+) m/z 409 (M+H).

Other compounds prepared by Method B as described for Example 2 using the appropriate starting materials are listed in TABLE 1

Example 3 3-Methyl-3H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide (Method C) i) (3-Benzylamino-phenyl)-carbamic acid tert-butyl ester

A solution of (3-amino-phenyl)-carbamic acid tert-butyl ester (1 g, 4.8 mmol), benzaldehyde (0.54 ml, 5.3 mmol) and acetic acid (0.41 ml, 7.2 mmol) in dry tetrahydrofuran (30 ml) were stirred at room temperature for 2 hrs. Sodium borohydride (0.172 g, 4.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO₂) eluting with ethyl acetate to afford the title compound as an off white solid (1.27 g, 89%) HPLC retention time 6.4 min. Mass spectrum (ES+) m/z 198 (M+H-BOC)

ii) [3-(Benzenesulfonyl-benzyl-amino)-phenyl]-carbamic acid tert-butyl ester

A solution of (3-benzylamino-phenyl)-carbamic acid tert-butyl ester (1.27 g, 4.3 mmol), benzenesulphonyl chloride (1.79 ml, 14 mmol) and pyridine (1.24 ml, 15.3 mmol) in dry dichloromethane (30 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and quenched with water and extracted with dichloromethane (3×75 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO₂) eluting with dichloromethane to afford the title compound as a brown oil (1.09 g, 58%). HPLC retention time 6.6 mins.

The following compounds were synthesized according to this method using the appropriate starting materials

-   1-Methyl-1H-imidazole-4-sulfonic acid benzyl-(3-bromo-phenyl)-amide -   Pyridine-3-sulfonic acid benzyl-(3-bromo-phenyl)-amide

iii) N-(3-Amino-phenyl)-N-benzyl-benzene sulfonamide

A solution of [3-(benzenesulfonyl-benzyl-amino)-phenyl]-carbamic acid tert-butyl ester (1.09 g, 2.49 mmol) and trifluoroacetic acid (2.5 ml) in dichloromethane (22.5 ml) were stirred at room temperature for 90 minutes. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo to afford the title compound as a brown oil (0.83 g, 99%). HPLC retention time 5.9 min.

iv) 3-Methyl-3H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide (3)

A solution of N-(3-amino-phenyl)-N-benzyl-benzene sulfonamide (25 mg, 0.07 mmol), 3-methyl-3H-imidazole-4-carboxylic acid (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine (25 μl, 0.18 mmol) in dry acetonitrile (1 ml) were stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (10 ml), extracted with dichloromethane (3×7 ml) and the combined organics concentrated in vacuo. The crude residue was purified by preparative TLC (SiO₂) eluting with ethyl acetate/dichloromethane (1:1) to afford the title compound as an off white solid (2.8 mg, 8%). HPLC retention time 5.6 min. Mass spectrum (ES+) m/z 447 (M+H).

Other compounds prepared by Method C as described for Example 3 using the appropriate starting materials are listed in TABLE 1

Example 4 1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-fluoro-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide (Method D) i) 1-(5-Amino-2-fluoro-phenyl)-pyrrolidin-2-one

2-Fluoro-5-nitroaniline (500 mg, 3.2 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) were stirred in dry dichloromethane (10 ml) under nitrogen. 4-Chlorobutyryl chloride was added drop-wise over 1 minute and the reaction was stirred for a further 2 hrs. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The organics were collected, dried (magnesium sulphate), concentrated in vacuo and the residue purified by flash column chromatography (SiO₂) eluting with dichloromethane to give 537 mg of 4-chloro-N-(2-fluoro-5-nitro-phenyl)-butyramide as a white solid. This material was re-dissolved in dry tetrahydrofuran and cooled over an ice-bath. Sodium hydride (83 mg, 2 mmol) was added and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 ml). The organics were washed with water (50 ml), dried (magnesium sulphate) and concentrated in vacuo to give 430 mg of crude 1-(2-fluoro-5-nitro-phenyl)-pyrrolidin-2-one as a yellow solid. This material was suspended in diethyl ether (20 ml) and ethanol (2 ml). A solution of tin (II) chloride dihydrate in concentrated HCl (20 ml) was added drop-wise over 5 minutes and the reaction stirred at room temperature for 3 hrs. The reaction mixture was neutralised to pH 7 by addition of 2M sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford crude 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (424 mg, 68%) as a yellow solid. HPLC retention time 3.3 min. Mass spectrum (ES+) m/z 195 (M+H).

ii) 1-[5-(4-Chloro-benzylamino)-2-fluoro-phenyl]-pyrrolidin-2-one

A solution of 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (0.34 g, 1.8 mmol), 4-chlorobenzaldehyde (0.25 g, 1.8 mmol) and sodium triacetoxyborohydride (0.75 g 3.6 mmol) was stirred in dry dichloromethane (25 ml) overnight. The reaction was quenched with water (25 ml) and the dichloromethane layer separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO₂) eluting with ethyl acetate/dichloromethane (1:10) to afford the title compound as a yellow oil (253 mg, 44%). HPLC retention time 4.4 min, Mass spectrum (ES+) m/z 319 (M+H).

iii) 1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-fluoro-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide (4)

1-[5-(4-Chloro-benzylamino)-2-fluoro-phenyl]-pyrrolidin-2-one (32 mg, 0.1 mmol), 1-methylimidazole-4-sulfonyl chloride (54 mg, 0.3 mmol) and pyridine (24 ul, 0.3 mmol) were refluxed in dry dichloromethane (3 ml) for 18 hrs. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to afford the title compound as a yellow oil (19.5 mg, 42%). HPLC retention time 4.3 min, Mass spectrum (ES+) m/z 464 (M+H).

Other compounds prepared by Method D as described for Example 4 using the appropriate starting materials are listed in TABLE 1

Example 5 N-Benzyl-N-[3-(4-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide (Method E)

A solution of N-benzyl-N-(3-bromo-phenyl)-benzene sulfonamide (25 mg, 0.06 mmol), 1-phenyl-piperazine (0.011 ml, 0.074 mmol), palladium acetate (1 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (2 mg) and sodium tert-butoxide (21 mg, 0.22 mmol) in dioxane (4 ml) were refluxed overnight. The reaction was quenched with water (5 ml) and extracted with dichloromethane (3×6 ml). The organic extracts were combined, filtered then concentrated in vacuo and the residues purified by preparative TLC (SiO₂) eluting with dichloromethane to afforded the title compound as a yellow solid (23 mg, 77%) HPLC retention time 9.4 min. Mass spectrum (ES+) m/z 484 (M+H).

Example 6 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(pyridin-2-yl methoxy)-phenyl]-amide (Method F) i) (4-Chloro-benzyl)-(3-methoxy-phenyl)-amine

4-Chlorobenzaldehyde (3.41 g, 27.5 mmol) was added to a cooled stirred solution of 3-methoxy aniline (3.38 g, 27.5 mmol) in anhydrous dichloromethane (120 ml). Sodium triacetoxy borohydride (8.16 g, 38.5 mmol) and acetic acid (1.57 ml, 27.5 mmol) were added and the reaction stirred under nitrogen at room temperature overnight. The reaction was quenched by the addition of 2 N sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (3×100 ml). The organic extracts were combined, washed with water (100 ml), brine (100 ml) and then concentrated in vacuo to obtain crude product. The residues were purified by flash chromatography (SiO₂) eluting with petrol/dichloromethane 3:1 to afford the title compound (4.4 g, 64% yield). HPLC retention time 8.4 min Mass spectrum (ES+) m/z 248 (M+H).

ii) 3-(4-Chloro-benzylamino)-phenol

Boron tribromide (2.59 ml, 27.4 mmol) was added drop wise to a cool stirred solution of (4-chloro-benzyl)-(3-methoxy-phenyl)-amine (2.37 g, 9.6 mmol) in anhydrous dichloromethane (90 ml) and the mixture was stirred at 0° C. for 1 hour then ambient for 15 hours. The reaction was cooled to 0° C. and quenched with the addition of saturated sodium bicarbonate solution (aq) (100 ml). The aqueous layer was collected and extracted further with dichloromethane (2×100 ml) and combined organic extracts were concentrated in vacuo to obtain crude product. The crude residue was purified by flash chromatography (SiO₂) eluting with 5% ethyl acetate/dichloromethane to yield a cream solid (1.58 g, 71% yield). HPLC retention time 4.55 min Mass spectrum (ES+) m/z 234 (M+H).

iii) 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide

Pyridine (520 μl, 6.4 mmol) was added to a stirred solution of 3-(4-chloro-benzylamino)-phenol (500 mg, 2.2 mmol) and 1-methylpyrazole-3-sulfonyl chloride (181 mg, 4.5 mmol) in anhydrous dichloromethane (22 ml). The reaction was stirred under nitrogen at 50° C. for 48 hours and then quenched with water (50 ml). The reaction was extracted with dichloromethane (3×25 ml), and the organics combined, washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate and then concentrated in vacuo. The crude product was dissolved in a solution of tetrahydrofuran/methanol/water (1:1:1) (25 ml), treated with lithium hydroxide (271 mg, 6.45 mmol) and the mixture was stirred at 85° C. for 2 hours. The reaction was cooled, quenched with 2M hydrochloric acid (aq) until slightly acidic and extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with water (100 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to obtain a white solid (645 mg, 27% yield). HPLC retention time 5.59 min Mass spectrum (ES+) m/z 378 (M+H).

iv) 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(pyridin-2-yl methoxy)phenyl]-amide (6)

2-(Bromomethyl)pyridine hydrochloride (33.4 mg, 0.13 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide (34 mg, 0.09 mmol), potassium iodide (21.9 mg, 0.13 mmol) and potassium carbonate (18.2 mg, 0.13 mmol) in anhydrous dimethyl formamide (2 ml). The reaction was stirred at ambient for 16 hours then concentrated in vacuo and purified by prep HLPC to obtain a yellow oil (10 mg, 16% yield). HPLC retention time 2.86 min Mass spectrum (ES+) m/z 470 (M+H).

Other compounds prepared by Method F as described for Example 6 using the appropriate starting materials are listed in TABLE 1

Example 7 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-N-methyl-acetamide (Method G) i) {3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-acetic acid tert-butyl ester

tert-Butyl bromoacetate (87.3 μl, 0.596 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide (150 mg, 0.40 mmol) and cesium carbonate (388 mg, 1.19 mmol) in anhydrous dimethyl formamide (10 ml) and then stirred at ambient for 16 hours. The reaction was diluted with ethyl acetate (10 ml), washed with water (3×20 ml) and the organic extracts were concentrated in vacuo to obtain crude product. The residue was purified by flash chromatography eluting with 10% methanol/dichloromethane to yield a yellow oil (163 mg, 56% yield). HPLC retention time 6.47 min Mass spectrum (ES+) m/z 509 (M+H).

ii) {3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-acetic acid

Trifluoroacetic acid (3.5 ml) was carefully added to a stirred solution of {3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-acetic acid tert-butyl ester (163 mg, 0.33 mmol) in anhydrous dichloromethane (7 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred at ambient for 3 hours then concentrated to obtain a yellow oil (212 mg, TFA salt). HPLC retention time 5.57 min Mass spectrum (ES+) m/z 437 (M+H).

iii) 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-N-methyl-acetamide (7)

Diisopropylethyl amine (48 μl, 0.28 mmol) was added to a stirred solution of {3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-phenoxy}-acetic acid (40 mg, 0.09 mmol), methylamine (46 μl, 2M in methanol, 0.9 mmol) and HATU (35 mg, 0.09 mmol) in anhydrous dimethylformamide (3 ml) and the reaction was stirred under nitrogen at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to afford a white solid (10 mg, 23% yield). HPLC retention time 2.69 min Mass spectrum (ES+) m/z 449 (M+H).

Other compounds prepared by Method G as described for Example 7 using the appropriate starting materials are listed in TABLE 1

TABLE 1 Summary of synthesis methods and characterisation data LCMS Ret. n (ES+) m/z Example Name Method time (M + H) 1 N-Benzyl-N-[3-(2-oxo-imidazolidin- A 8.8 425 1-yl)-phenyl]-benzenesulfonamide 2 N-Benzyl-N-(3-morpholin-4-yl- B 8.3 409 phenyl)-benzenesulfonamide 3 3-Methyl-3H-imidazole-4-carboxylic C 5.6 447 acid [3-(benzenesulfonyl-benzyl- amino)-phenyl]-amide 4 1-Methyl-1H-imidazole-4-sulfonic D 4.3 464 acid (4-chloro-benzyl)-[4-fluoro-3- (2-oxo-pyrrolidin-1-yl)-phenyl]- amide 5 N-Benzyl-N-[3-(4-phenyl-piperazin- E 9.4 484 1-yl)-phenyl]-benzenesulfonamide 6 1-Methyl-1H-pyrazole-3-sulfonic F 2.86 470 acid (4-chloro-benzyl)-[3-(pyridin-2- yl methoxy)-phenyl]-amide 7 2-{3-[(4-Chloro-benzyl)-(1-methyl- G 2.69 449 1H-pyrazole-3-sulfonyl)-amino]- phenoxy}-N-methyl-acetamide 8 N-[3-(Benzenesulfonyl-benzyl- C 5.65 398 (NH₃ salt) amino)-phenyl]-acetamide 9 N-[3-(Benzenesulfonyl-benzyl- C 6.32 474 amino)-phenyl]-2-phenyl-acetamide 10 N-[3-(Benzenesulfonyl-benzyl- C 5.86 428 amino)-phenyl]-2-methoxy- acetamide 11 1-Methyl-1H-imidazole-4-sulfonic B 8.3 488 acid benzyl-[3-(4-phenyl-piperazin- 1-yl)-phenyl]-amide 12 N-Benzyl-N-[3-(3-phenyl-piperazin- E 8.3 484 1-yl)-phenyl]-benzenesulfonamide 13 Pyridine-3-sulfonic acid benzyl-[3- B 8.7 485 (4-phenyl-piperazin-1-yl)-phenyl]- amide 14 3-Oxo-3,4-dihydro-2H- D 7.5 478 benzo[1,4]oxazine-6-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)- phenyl]-amide 15 4-Methyl-3,4-dihydro-2H- D 8.05 478 benzo[1,4]oxazine-7-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)- phenyl]-amide 16 1,2-Dimethyl-1H-imidazole-4- A 7.3 427 sulfonic acid benzyl-(3-morpholin-4- yl-phenyl)-amide 17 N-Benzyl-3-cyano-N-(3-morpholin- A 8.2 434 4-yl-phenyl)-benzenesulfonamide 18 4-Methyl-3,4-dihydro-2H- A 8.3 480 benzo[1,4]oxazine-7-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)- amide 19 N-Benzyl-3-cyano-N-[3-(2-oxo- D 7.9 449 pyrrolidin-1-yl)-phenyl]- benzenesulfonamide 20 N-Benzyl-N-[3-(2-oxo-imidazolidin- A 8.8 425 1-yl)-phenyl]-benzenesulfonamide 21 1-Methyl-1H-pyrazole-4-sulfonic D 7.46 408 acid benzyl-[3-(2-oxo-pyrrolidin-1- yl)-phenyl]-amide 22 1,2-Dimethyl-1H-imidazole-4- D 7.43 459 sulfonic acid (4-chloro-benzyl)-[3-(2- oxo-pyrrolidin-1-yl)-phenyl]-amide 23 2-Methyl-2H-pyrazole-3-sulfonic D 7.98 445 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 24 4-Methyl-3,4-dihydro-2H- D 8.33 512 benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 25 1-Methyl-1H-pyrazole-4-sulfonic D 7.67 462 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 26 3-Oxo-3,4-dihydro-2H- D 7.8 512 benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 27 N-(4-Chloro-benzyl)-3-cyano-N-(3- A 8.41 468 morpholin-4-yl-phenyl)- benzenesulfonamide 28 2-Methyl-2H-pyrazole-3-sulfonic A 8.25 447 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 29 4-Methyl-3,4-dihydro-2H- A 7.99 461 benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl- phenyl)-amide 30 1-Methyl-1H-pyrazole-4-sulfonic A 7.88 447 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 31 3-Oxo-3,4-dihydro-2H- A 7.99 514 benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl- phenyl)-amide 32 Pyridine-3-sulfonic acid (4-chloro- A 8.06 444 benzyl)-(3-morpholin-4-yl-phenyl)- amide 33 1-Methyl-1H-imidazole-4-sulfonic A 7.7 447 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 34 1-Methyl-1H-pyrazole-3-sulfonic D 5.66 463 acid (4-chloro-benzyl)-[4-fluoro-3- (2-oxo-pyrrolidin-1-yl)-phenyl]- amide 35 1-Methyl-1H-pyrazole-3-sulfonic D 5.71 445 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 36 1-Methyl-1H-pyrazole-3-sulfonic D 5.39 411 acid benzyl-[3-(2-oxo-pyrrolidin-1- yl)-phenyl]-amide 37 1-Methyl-1H-pyrazole-3-sulfonic A 5.95 447 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 38 1-Methyl-1H-pyrazole-3-sulfonic A 5.62 413 acid benzyl-(3-morpholin-4-yl- phenyl)-amide 39 1-Methyl-1H-pyrazole-3-sulfonic A 5.4 446 acid (4-chloro-benzyl)-[3-(2-oxo- imidazolidin-1-yl)-phenyl]-amide 40 1-Methyl-1H-pyrazole-3-sulfonic A 5.12 412 acid benzyl-[3-(2-oxo-imidazolidin- 1-yl)-phenyl]-amide 41 N-Benzyl-3-cyano-4-fluoro-N-[3-(2- A 9.02 468 oxo-imidazolidin-1-yl)-phenyl]- benzenesulfonamide 42 N-(4-Chloro-benzyl)-3-cyano-4- A 7.95 485 fluoro-N-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-benzenesulfonamide 43 N-(4-Chloro-benzyl)-N-[3-(2-oxo- A 7.96 442 imidazolidin-1-yl)-phenyl]- benzenesulfonamide 44 Pyridine-3-sulfonic acid benzyl-[3- A 2.5 409 (2-oxo-imidazolidin-1-yl)-phenyl]- a(2-oxo-imidazolidin-1-yl)-phenyl]- amide 45 Pyridine-3-sulfonic acid (4-chloro- A 2.68 443 benzyl)-[3-(2-oxo-imidazolidin-1- ylbenzyl)-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-amide 46 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- G 3.01 513 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-pyridin-2-yl-acetamide 47 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- G 3.03 490 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-cyclobutyl-acetamide 48 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- G 2.69 476 pyrazole-3-sulfonyl)-amino]- phenoxy}-N-cyclopropyl-acetamide

Example 49 Kv1.3 Autopatch Electrophysiology Method

Cells stably transfected with cDNA for human Kv1.3 (in pcDNA3.1) were grown in Ex-cell 302 serum-free medium for CHO cells, supplemented with 10 μl/ml [100×] glutamine, 500 μg/ml G418 (gentimicin), and 1% HT supplement (50×, hypoxanthine and thymidine). Compounds were tested on these cells using the AutoPatch technology in whole cell mode.

The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 1 MgCl₂, 3 CaCl₂, 10 HEPES, pH 7.4 with NaOH. Patch pipettes were filled with an electrode solution of composition (in mM): 100 K-Gluconate, 20 KCl, 1 MgCl₂, 1 CaCl₂, 10 HEPES, 11 EGTA, 5 ATP-Na₂, 2 Glutathione pH 7.2 with KOH.

Compounds were dissolved in DMSO (100%) and made up in the external bather at a concentration of 1 μM immediately prior to use. All experiments were conducted at room temperature.

A cell suspension (10 ml), with a density of 6×10⁶ cells, was aliquoted into a 15 ml centrifuge tube and stored at 4° C. before use. Prior to use a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. The supernatant was then discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 1 ml of cold (4° C.), filtered (0.22 μm), 0.05% BSA/bather solution (0.05 g BSA/100 ml bather). The bottom of the tube was manually agitated followed by gentle tituration. The cell suspension was then placed in the AutoPatch™ temperature controlled cell-hotel at 14° C. and regularly titurated.

A length of Teflon capillary tubing was dipped into the cell suspension solution, and a column of fluid was taken up by negative pressure. The column of fluid was in electrically connectivity with a Ag/AgCl reference electrode. Borosilicate glass patch pipettes (from 1.5 mm OD, thin-walled filamented, GC150-TF capillary glass, Harvard) were pulled using a DMZ pipette puller (Zeitz Instruments), and were back-filled using the internal pipette solution, being careful that no bubbles remained at the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.5-3.5 MΩ. Once filled, the pipette tip and a proportion of the shaft (˜15 mm) were dipped into Sigmacote (Sigma). The recording pipettes were placed in a multiwell array and mounted on the AutoPatch™ machine. Automated patch-clamping and drug-application was initiated by the operator, but thereafter AutoPatch.exe continued the experiment providing that pre-set conditions and criteria were satisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig, which incorporated an EPC9 or EPC10 amplifier (HEKA, Germany) under control of Pulse software (v8.54 or v8.76, HEKA, Germany), a cell applicator, automated drug application system (DAS), valve controller (VF1) and a suction device all at room temperature. This equipment was completely under the control of AutoPatch.exe and operator intervention was only made when there was a requirement to refill the bather reservoirs or to prevent the loss of a cell due to a technical error.

Qualification stages prior to perfusion and drug application ensured that the observed current met the criteria for the experiment. Cells were continuously perfused with external solution at a flow rate of ˜2 ml/minute. The perfusion chamber had a working volume of 80-85 μl that allowed for rapid exchange of drug solutions.

Electrophysiology voltage-step protocols and analysis of data was performed as follows. Data were sampled at 5 kHz, and filtered with a −3 dB bandwidth of 2.5 kHz. Cells were held at a voltage of −80 mV. Currents were evoked by a voltage step to +30 mV for 500 ms in duration applied every 15 s. Online analysis of the hKv1.3 current during the application of compounds was performed by the Pulse (v8.54 or v8.76, HEKA, Germany), Excel (Microsoft, USA) and AutoPatch™ software, with the total charge measured during the whole of voltage step Inhibition of charge movement in the presence of drug was calculated relative to control.

Example 50 Summary of Kv1.3 Biological Activity

hKv1.3 Example Name % inh. 1 N-Benzyl-N-[3-(2-oxo-imidazolidin- 86 1-yl)-phenyl]-benzenesulfonamide 2 N-Benzyl-N-(3-morpholin-4-yl- 76 phenyl)-benzenesulfonamide 3 3-Methyl-3H-imidazole-4-carboxylic 90 acid [3-(benzenesulfonyl-benzyl- amino)-phenyl]-amide 4 1-Methyl-1H-imidazole-4-sulfonic 61 acid (4-chloro-benzyl)-[4-fluoro-3- (2-oxo-pyrrolidin-1-yl)-phenyl]- amide 5 N-Benzyl-N-[3-(4-phenyl-piperazin- 88 1-yl)-phenyl]-benzenesulfonamide 6 1-Methyl-1H-pyrazole-3-sulfonic 91 acid (4-chloro-benzyl)-[3-(pyridin-2- yl methoxy)-phenyl]-amide 7 2-{3-[(4-Chloro-benzyl)-(1-methyl- 99 1H-pyrazole-3-sulfonyl)-amino]- phenoxy}-N-methyl-acetamide 10 N-[3-(Benzenesulfonyl-benzyl- 50 amino)-phenyl]-acetamide 11 N-[3-(Benzenesulfonyl-benzyl- 86 amino)-phenyl]-2-phenyl-acetamide 12 N-[3-(Benzenesulfonyl-benzyl- 85 amino)-phenyl]-2-methoxy- acetamide 13 1-Methyl-1H-imidazole-4-sulfonic 41 acid benzyl-[3-(4-phenyl-piperazin- 1-yl)-phenyl]-amide 14 N-Benzyl-N-[3-(3-phenyl-piperazin- 94 1-yl)-phenyl]-benzenesulfonamide 16 Pyridine-3-sulfonic acid benzyl-[3- 97 (4-phenyl-piperazin-1-yl)-phenyl]- amide 18 4-Methyl-3,4-dihydro-2H- 65 benzo[1,4]oxazine-7-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)- phenyl]-amide 19 1,2-Dimethyl-1H-imidazole-4- 75 sulfonic acid benzyl-(3-morpholin-4- yl-phenyl)-amide 23 N-Benzyl-N-[3-(2-oxo-imidazolidin- 86 1-yl)-phenyl]-benzenesulfonamide 36 1-Methyl-1H-imidazole-4-sulfonic 83 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 37 1-Methyl-1H-pyrazole-3-sulfonic 53 acid (4-chloro-benzyl)-[4-fluoro-3- (2-oxo-pyrrolidin-1-yl)-phenyl]- amide 38 1-Methyl-1H-pyrazole-3-sulfonic 96 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 39 1-Methyl-1H-pyrazole-3-sulfonic 74 acid benzyl-[3-(2-oxo-pyrrolidin-1- yl)-phenyl]-amide 40 1-Methyl-1H-pyrazole-3-sulfonic 99 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 41 1-Methyl-1H-pyrazole-3-sulfonic 92 acid benzyl-(3-morpholin-4-yl- phenyl)-amide 42 1-Methyl-1H-pyrazole-3-sulfonic 99 acid (4-chloro-benzyl)-[3-(2-oxo- imidazolidin-1-yl)-phenyl]-amide 43 1-Methyl-1H-pyrazole-3-sulfonic 72 acid benzyl-[3-(2-oxo-imidazolidin- 1-yl)-phenyl]-amide 44 N-Benzyl-3-cyano-4-fluoro-N-[3-(2- 90 oxo-imidazolidin-1-yl)-phenyl]- benzenesulfonamide 45 N-(4-Chloro-benzyl)-3-cyano-4- 100 fluoro-N-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-benzenesulfonamide 46 N-(4-Chloro-benzyl)-N-[3-(2-oxo- 100 imidazolidin-1-yl)-phenyl]- benzenesulfonamide 47 Pyridine-3-sulfonic acid benzyl-[3- 74 (2-oxo-imidazolidin-1-yl)-phenyl]- a(2-oxo-imidazolidin-1-yl)-phenyl]- amide 48 Pyridine-3-sulfonic acid (4-chloro- 96 benzyl)-[3-(2-oxo-imidazolidin-1- ylbenzyl)-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-amide 49 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 95 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-pyridin-2-yl-acetamide 50 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 94 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-cyclobutyl-acetamide 51 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 83 pyrazole-3-sulfonyl)-amino]- phenoxy}-N-cyclopropyl-acetamide

Example 51 Kv1.5 Autopatch Electrophysiology Method

The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 100 Potassium Gluconate, 3 MgCl₂, 1 CaCl₂, 10 HEPES, pH 7.4. Patch pipettes were filled with an electrode solution of composition (in mM): 160 KCl, 0.5 MgCl₂, 10 HEPES, 1 EGTA, pH 7.4 with KOH.

Compounds were dissolved in DMSO (100%) and made up in the external bather at a concentration of 1 μM. All experiments were conducted at room temperature (22-24° C.).

A cell suspension (10 ml), with a density of 100,000 cells/ml, was aliquoted into a 15 ml centrifuge tube and transferred to an incubator (37° C., 5% CO₂) for approximately one hour before use. Following 60 min incubation, a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. 9.5 ml supernatant was thence discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 100 μl of cold (4° C.), filtered (0.22 μm), 0.2% BSA/bather solution (0.02 g BSA/10 ml bather). The bottom of the tube was manually agitated gently until the solution became cloudy with cells. The 100 μl cell resuspension solution was then stored on the bench at 4° C. (using a Peltier-based temperature control device) until used.

A length of capillary glass (1B150E-4, WPI) was dipped into the cell suspension solution, such that ˜3 cm column of fluid was taken up by capillary action. A Ag/AgCl wire was dropped into the non-dipped end of the capillary also. The outside of the solution-filled end of the capillary was then dried and the capillary was loaded into the AutoPatch™

Borosilicate glass patch pipettes (from 1.5 mm OD, thin-walled filamented, GC150-TF capillary glass, Harvard) were pulled using a DMZ pipette puller (Zeitz Instruments), and were back-filled using the internal pipette solution, being careful that no bubbles remain at the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.3-3.5 MΩ. Once filled, the pipette tip and a proportion of the shaft (˜15 mm) were dipped into Sigmacote (Sigma). The recording pipette was then loaded into the AutoPatch™. Automated patch-clamping was initiated by the operator, but thereafter AutoPatch.exe continued the experiment providing that pre-set conditions and criteria were satisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig, which incorporated an EPC9 amplifier (HEKA, Germany) under control of Pulse software (v8.54, HEKA, Germany), a motion controller with 2 translators (Newport, UK), valve controller (VF1) and a c-level suction device all at room temperature (22-24° C.). This equipment was completely under the control of AutoPatch.exe and operator intervention was only made when there was a requirement to refill the drug reservoirs or to prevent the loss of a cell due to a technical error. Cells with an R_(series) greater than 18 MΩ were discounted from the experiment.

Qualification stages prior to perfusion and drug application ensured that the observed current met the criteria for the experiment. Only those cells with an I_(K)>500 pA were used for experiments. Cells were continuously perfused with external solution at a flow rate of 1.8-2 ml/minute. The perfusion chamber had a working volume of 80-85 μl and allowed for rapid exchange of drug solutions. Online analysis of the hK_(v)1.5 current during the application of compounds was performed by the AutoPatch™ software. Voltage-step protocols and analysis of data was performed as described for conventional electrophysiology.

Electrophysiology voltage-step protocols and analysis of data was performed as follows. Data was sampled at 5 kHz, and filtered with a −3 dB bandwidth of 2.5 kHz. Cells were held at a voltage of −80 mV. Currents were evoked to a voltage step for 1000 ms in duration at 0 mV every 5 s. Currents were analysed using Pulsefit software (v8.54, HEKA, Germany), with the total charge measured during the whole of the voltage step. All other plots were produced using Igor Pro (WaveMetrics).

Example 52 Summary of Kv1.5 Biological Activity

hKv1.5 Example Name % inh. 1 N-Benzyl-N-[3-(2-oxo-imidazolidin- 66 1-yl)-phenyl]-benzenesulfonamide 2 N-Benzyl-N-(3-morpholin-4-yl- 62 phenyl)-benzenesulfonamide 3 3-Methyl-3H-imidazole-4-carboxylic 73 acid [3-(benzenesulfonyl-benzyl- amino)-phenyl]-amide 5 N-Benzyl-N-[3-(4-phenyl-piperazin- 91 1-yl)-phenyl]-benzenesulfonamide 6 1-Methyl-1H-pyrazole-3-sulfonic 72 acid (4-chloro-benzyl)-[3-(pyridin-2- yl methoxy)-phenyl]-amide 7 2-{3-[(4-Chloro-benzyl)-(1-methyl- 93 1H-pyrazole-3-sulfonyl)-amino]- phenoxy}-N-methyl-acetamide 10 N-[3-(Benzenesulfonyl-benzyl- 28 amino)-phenyl]-acetamide 11 N-[3-(Benzenesulfonyl-benzyl- 77 amino)-phenyl]-2-phenyl-acetamide 12 N-[3-(Benzenesulfonyl-benzyl- 58 amino)-phenyl]-2-methoxy- acetamide 14 N-Benzyl-N-[3-(3-phenyl-piperazin- 77 1-yl)-phenyl]-benzenesulfonamide 16 Pyridine-3-sulfonic acid benzyl-[3- 91 (4-phenyl-piperazin-1-yl)-phenyl]- amide 17 3-Oxo-3,4-dihydro-2H- 45 benzo[1,4]oxazine-6-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)- phenyl]-amide 18 4-Methyl-3,4-dihydro-2H- 56 benzo[1,4]oxazine-7-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)- phenyl]-amide 19 1,2-Dimethyl-1H-imidazole-4- 42 sulfonic acid benzyl-(3-morpholin-4- yl-phenyl)-amide 20 N-Benzyl-3-cyano-N-(3-morpholin- 90 4-yl-phenyl)-benzenesulfonamide 21 4-Methyl-3,4-dihydro-2H- 72 benzo[1,4]oxazine-7-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)- amide 22 N-Benzyl-3-cyano-N-[3-(2-oxo- 82 pyrrolidin-1-yl)-phenyl]- benzenesulfonamide 23 N-Benzyl-N-[3-(2-oxo-imidazolidin- 66 1-yl)-phenyl]-benzenesulfonamide 24 1-Methyl-1H-pyrazole-4-sulfonic 41 acid benzyl-[3-(2-oxo-pyrrolidin-1- yl)-phenyl]-amide 25 1,2-Dimethyl-1H-imidazole-4- 39 sulfonic acid (4-chloro-benzyl)-[3-(2- oxo-pyrrolidin-1-yl)-phenyl]-amide 26 2-Methyl-2H-pyrazole-3-sulfonic 43 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 27 4-Methyl-3,4-dihydro-2H- 84 benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 28 1-Methyl-1H-pyrazole-4-sulfonic 49 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 29 3-Oxo-3,4-dihydro-2H- 72 benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 30 N-(4-Chloro-benzyl)-3-cyano-N-(3- 97 morpholin-4-yl-phenyl)- benzenesulfonamide 31 2-Methyl-2H-pyrazole-3-sulfonic 47 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 32 4-Methyl-3,4-dihydro-2H- 64 benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl- phenyl)-amide 33 1-Methyl-1H-pyrazole-4-sulfonic 58 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 34 3-Oxo-3,4-dihydro-2H- 68 benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl- phenyl)-amide 35 Pyridine-3-sulfonic acid (4-chloro- 84 benzyl)-(3-morpholin-4-yl-phenyl)- amide 36 1-Methyl-1H-imidazole-4-sulfonic 44 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 38 1-Methyl-1H-pyrazole-3-sulfonic 71 acid (4-chloro-benzyl)-[3-(2-oxo- pyrrolidin-1-yl)-phenyl]-amide 40 1-Methyl-1H-pyrazole-3-sulfonic 95 acid (4-chloro-benzyl)-(3-morpholin- 4-yl-phenyl)-amide 41 1-Methyl-1H-pyrazole-3-sulfonic 33 acid benzyl-(3-morpholin-4-yl- phenyl)-amide 42 1-Methyl-1H-pyrazole-3-sulfonic 77 acid (4-chloro-benzyl)-[3-(2-oxo- imidazolidin-1-yl)-phenyl]-amide 44 N-Benzyl-3-cyano-4-fluoro-N-[3-(2- 72 oxo-imidazolidin-1-yl)-phenyl]- benzenesulfonamide 45 N-(4-Chloro-benzyl)-3-cyano-4- 95 fluoro-N-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-benzenesulfonamide 46 N-(4-Chloro-benzyl)-N-[3-(2-oxo- 91 imidazolidin-1-yl)-phenyl]- benzenesulfonamide 47 Pyridine-3-sulfonic acid benzyl-[3- 51 (2-oxo-imidazolidin-1-yl)-phenyl]- a(2-oxo-imidazolidin-1-yl)-phenyl]- amide 48 Pyridine-3-sulfonic acid (4-chloro- 89 benzyl)-[3-(2-oxo-imidazolidin-1- ylbenzyl)-[3-(2-oxo-imidazolidin-1- yl)-phenyl]-amide 49 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 99 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-pyridin-2-yl-acetamide 50 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 79 pyrazole-3-sulfonyl)-amino]- phenoxy}- N-cyclobutyl-acetamide 51 2-{3-[(4-Chloro-benzyl)-(1-methyl-1H- 72 pyrazole-3-sulfonyl)-amino]- phenoxy}-N-cyclopropyl-acetamide

REFERENCES

-   Herbert, “General principles of the structure of ion channels”,     Am. J. Med, 104, 87-98, 1998. -   Armstrong & Hille, “Voltage-gated ion channels and electrical     excitability”, Neuron, 20, 371-380, 1998. -   Gutman G A et al., “International Union of Pharmacology. XLI.     Compendium of voltage-gated ion channels: potassium channels”.     Pharmacol Rev. December; 55(4):583-6, 2003. -   Shieh et al., “Potassium Channels: Molecular Defects, Diseases, and     Therapeutic Opportunities”, Pharmacol Rev, 52(4), 557-594, 2000. -   Ford et al., “Potassium Channels: Gene Family, Therapeutic     Relevance, High-Throughput Screening Technologies and Drug     Discovery”, Prog Drug Res, 58, 133-168, 2002. -   Xie M et al., “Ion Channel Drug Discovery Expands into New Disease     Areas”, Current Drug Discovery, 31-33, 2004. -   Cahalan M D & Chandy K G, “Ion Channels in the Immune System as     Targets for Immunosuppression”, Current Opinion in Biotechnology, 8,     749-756, 1997. -   Beeton et al., “Kv1.3 channels are a therapeutic target for     T-cell-mediated autoimmune diseases”, Proceeds of the National     Academy of Sciences, 46, 103, 17414-17419, 2006 -   Wulff H, Beeton C, Chandy K G: Potassium channels as therapeutic     targets for autoimmune disorders. (2003) Curr. Opin. Drug Dis.     6(5):640-647 -   Beeton C, Pennington M W, Wulff H, Singh S, Nugent D, Crossley G,     Khaytin I, Calabresi P A, Chen C Y, Gutman G A, Chandy K G.     Targeting effector memory T-cells with a selective peptide inhibitor     of Kv1.3 channels for therapy of autoimmune diseases. (2005) Mol.     Pharmacol. 67(4): 1369-81. -   Panyi G, Varga Z, Gaspar R. Abstract Ion channels and lymphocyte     activation. (2004) Immunology Lett. 92:55-66. -   Chandy K G, Wulff H, Beeton C, Pennington M, Gutman G, Cahalan M: K+     channels as targets for specific immunomodulation. TIPS. (2004)     25(5):280-289 -   Beeton C, Barbaria J, Giraud P, Devaux J, Benoliel A, Gola M,     Sabatier J M, Bernard D, Crest M, Beraud E: Selective blocking of     voltage-gated K+ channel improves experimental autoimmune     encephalomyelitis and inhibits T-cell activation. (2001) J. Immunol.     166:936-944 -   Price M J, Lee S C, Deutsch C: Charybdotoxin inhibits proliferation     and interleukin-2 production of human peripheral blood     lymphocytes. (1989) Proc. Natl. Acad. Sci. 86:10171-10175 -   Koo G C, Blake J T, Shah K, Staruch M J, Dumont F, Wunderler D L,     Sanchez M, McManus O B, Sirontina-Meisher A, Fischer P, Boltz R C,     Goetz M A, Baker R, Bao J, Kayser F, Rupprecht K M, Parsons W H,     Tong X, Ita I E, Pivnichny J, Vincent S, Cunningham P, Hora D,     Feeney W, Kaczorowski G, Springer M S: Correolide and derivatives     are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium     channels. (1999) Cell. Immunol., 197:99-107 -   Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D,     Hansel W, Wulff H: Design of PAP-1, a selective small molecule Kv1.3     blocker, for the suppression of effector memory cells in autoimmune     diseases. (2005) Mol. Pharmacol., 68:1254-1270 -   Triggle D. J, Gopalakkrishnan M, Rampe D, Zheng W: Voltage gated Ion     channels as Drug Targets, Wiley, 2005) -   Sands et al: Charabydotoxin blocks voltage-gated K+ channels in     human and murine T lymphocytes. J. Gen-Physiol. 1989, 93,     10061-1074. -   Garcia et al, Purification, characterisation and biosynthesis of     margatoxin, a component of Centruroides maragritatus venom that     selectively inhibits voltage-gated potassium channels, J. Biol.     Chem. 1993, 268, 18866-1887 -   Garcia et al: Purification and characterisation of three inhibitors     of voltage dependent K+ channels from Leiurus quinquesttriatus var.     hebraeus. Biochemistry, 1994, 33, 6834-6839 -   Koshchak et al., Subunit composition of brain voltage-gated     potassium channels determined by hongotoxin-1, a novel peptide     derived from Centruroides limbatus venom. J. Biol. Chem. 1998, 273,     2639-2644. -   Peter et al, Effect of toxins Pi2 and Pi3 on human T Lymphocyte     kv1.3 channels: the role of Glu7 and Lys24. J. Membr. Biol. 2001,     179, 13-25 -   Mouhat et al, K+ channel types targeted by synthetic OSK1, a toxin     from Orthochirus scrobiculosus scorpion venom Biochem. J. 2005, 385,     95-104 -   Pennington et al, Identification of there separate binding sites on     Shk toxin, a potent inhibitor of voltage dependent potassium     channels in human T-lymphocytes and rat brain. Biochem. Biophys.     Res. Commun. 1996, 219, 696-701 -   Pennington et al, ShK-Dap²², a potent Kv1.3-specific     immunosuppressive polypeptide. J. Biol. Chem. 1998, 273, 32697-35707 -   Nguyen A et al., “Novel Nonpeptide Agents Potently Block the C-Type     Inactivated Conformation of Kv1.3 and Suppress T-cell Activation”,     Mol. Pharmacol., 50, 1672-1679, 1996. -   Hanson D C et al., “UK-78,282, a Novel Piperidine Compound That     Potently Blocks the Kv1.3 Voltage-Gated Potassium Channel and     Inhibits Human T-cell Activation”, Br. J. Pharmacol., 126,     1707-1716, 1999. -   Felix J P et al., “Identification and Biochemical Characterization     of a Novel Norterpene Inhibitor of the Human Lymphocyte     Voltage-Gated Potassium Channel, Kv1.3”, Biochemistry, 38 (16),     4922-4930, 1999. -   Baell J B et al., “Khellinone Derivatives as Blockers of the     Voltage-Gated Potassium Channel Kv1.3: Synthesis and     Immunosuppressive Activity” J. Med. Chem., 47, 2326-2336, 2004. -   Wulff H et al., “Alkoxypsoralens, Novel Nonpeptide Blockers of     Shaker-Type K+ Channels: Synthesis and Photoreactivity”, J. Med.     Chem., 41, 4542-4549, 1998. -   Vennekamp J, Wulff H, Beeton C, Calabresi P A, Grissmer S, Hansel W,     and Chandy K G. Kv1.3-blocking 5-phenylalkoxypsoralens: a new class     of immunomodulators. (2004) Mol. Pharmacol. 65, 1364-74. -   Marban “Cardiac channelopalthies”, Nature, 415, 213-218, 213-218,     2002 -   Brendel and Peukert ‘Blockers of the Kv1.5 Channel for the Treatment     of Atrial Arrhythmias’, Expert Opinion in Therapeutic Patents, 12     (11), 1589-1598 (2002). -   Wang et al., “Sustained depolarization-induced outward current in     human atrial myocytes. Evidence for a novel delayed rectifier K+     current similar to Kv1.5 cloned channel currents”, Circ Res, 73,     1061-1076, 1993. -   Fedida et al., “Identity of a novel delayed rectifier current from     human heart with a cloned K+ channel current”, Circ Res, 73,     210-216, 1993. -   Feng et al., “Antisense oligodeoxynucleotides directed against Kv1.5     mRNA specifically inhibit ultrarapid delayed rectifier K+ current in     cultured adult human atrial myocytes”, Circ Res, 80, 572-579, 1997. -   Amos et al., “Differences between outward currents of human atrial     and subepicardial ventricular myocytes”, J Physiol, 491, 31-50,     1996. -   Li et al., “Evidence for two components of delayed rectifier K+     current in human ventricular myocytes”, Circ Res, 78, 689-696, 1996. -   Nattel, ‘Therapeutic implications of atrial fibrillation mechanisms:     can mechanistic insights be used to improve AF management?’     Cardiovascular Research, Volume 54, (2), 347-360, 2002. -   Courtemanche et al., “Ionic targets for drug therapy and atrial     fibrillation-induced electrical remodeling: insights from a     mathematical model”, Cardiovasc Res, 42(2), 477-489, 1999. -   Nattel et al., “Cardiac ultrarapid delayed rectifiers: a novel     potassium current family of functional similarity and molecular     diversity”, Cell Physiol Biochem, 9(4-5), 217-226, 1999. -   Knobloch K. et al. Electrophysiological and antiarrhythmic effects     of the novel I(Kur) channel blockers, S9947 and S20951, on left vs.     right pig atrium in vivo in comparison with the I(Kr) blockers     dofetilide, azimilide, d,l-sotalol and ibutilide. Naunyn     Schmiedebergs Arch Pharmacol. November; 366(5):482-7, 2002. -   Wirth K J et al., Atrial effects of the novel K(+)-channel-blocker     AVE0118 in anesthetized pigs. Cardiovasc Res. November 1; 60     (2):298-306, 2003. -   Colatsky et al., “Channel specificity in antiarrhythmic drug action.     Mechanism of potassium channel block and its role in suppressing and     aggravating cardiac arrhythmias”, Circulation, 82(6), 2235-2242,     1990. -   Feng et al., “Effects of class III antiarrhythmic drugs on transient     outward and ultra-rapid delayed rectifier currents in human atrial     myocytes”, J Pharmacol Exp Ther, 281(1), 384-392, 1997. -   Wang et al., “Effects of flecainide, quinidine, and 4-aminopyridine     on transient outward and ultrarapid delayed rectifier currents in     human atrial myocytes”, J Pharmacol, 272(1), 184-196, 1995. -   Malayev et al., “Mechanism of clofilium block of the human Kv1.5     delayed rectifier potassium channel”, Mol Pharmaco, 147(1), 198-205,     1995. -   Godreau et al., “Mechanisms of action of antiarrhythmic agent     bertosamil on hKv1.5 channels and outward potassium current in human     atrial myocytes”, J Pharmacol Exp Ther 300(2), 612-620, 2002. -   Matsuda et al., “Inhibition by a novel anti-arrhythmic agent,     NIP-142, of cloned human cardiac K⁺ channel Kv1.5 current”, Life     Sci, 68, 2017-2024, 2001. -   Bachmann et al., “Characterization of a novel Kv1.5 channel blocker     in Xenopus oocytes, CHO cells, human and rat cardiomyocytes”, Naunyn     Schmiedebergs Arch Pharmacol, 364(5), 472-478, 2001. -   Peukert S, et al., Identification, synthesis, and activity of novel     blockers of the voltage-gated potassium channel Kv1.5. J Med. Chem.     February 13; 46 (4):486-98, 2003. -   Mitsunobu, O “The Use of Diethyl Azodicarboxylate and     Triphenylphosphine in Synthesis and Transformation of Natural     Products”, Synthesis, 1-28. (Review) 

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X₁ is selected from a group consisting of CH, O and N; R₁ is selected from the group consisting of optionally substituted arylalkyl and optionally substituted heteroarylalkyl; R₂ is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl and NR₆R₇; R₃ is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulphonyl and nitrile; R₄ is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl; R₅ is hydrogen or when X₁ is N, R₅ together with R₄ and X₁, form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II):

wherein: each X₂ is independently C(═O), CH₂, CH(R_(8a)) or C(R_(8a))(R_(8b)); X₃ is CH₂, CH(R_(9a)), C(R_(9a))(R_(9b)), NH, N(R_(9c)), O or S; R₆ and R₇ are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; R_(8a) and R_(8b) independently represent halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxy, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; R_(9a) and R_(9b) independently represent halogen, optionally substituted amino, optionally substituted amino carbonyl, hydroxy, optionally substituted acyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; R_(9c) is optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl; n=1, 2 or 3; and j is 0 or 1; provided that: when X₁ is O then j=0; and when X₁ is N or CH then j=1.
 2. A compound according to claim 1 wherein: R₂ is NR₆R₇, or a pharmaceutically acceptable salt thereof.
 3. A compound as claimed in claim 2 wherein R₆ and R₇ are the same or different and each represents hydrogen or optionally substituted C₁₋₃ alkyl, or a pharmaceutically acceptable salt thereof.
 4. A compound according to claim 1 wherein: R₂ is selected from the group consisting of Formula (III), (IV) and (V):

wherein: A, Q, T, D, and E are the same or different and each represents C or N with the provisos that in each instance 1) at least one of A, Q, T, D, or E is N; 2) when R₂ is formula (III), E may also represent O or S; and 3) when R₂ is formula (IV), A may also represent O or S; and R₁₁ and R₁₂ are the same or different and each represents hydrogen, halogen, hydroxy, nitrile, optionally substituted amino, optionally substituted acyl, optionally substituted C₁₋₃ alkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring, or a pharmaceutically acceptable salt thereof.
 5. A compound as claimed in claim 4 wherein R₁₁ and R₁₂ are each CH₃, or a pharmaceutically acceptable salt thereof.
 6. A compound according to claim 1 wherein: R₂ is Formula (VI):

wherein: R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are the same or different and each represents hydrogen, halogen, hydroxy, optionally substituted amino, optionally substituted acyl, nitrile, or optionally substituted C₁₋₃ alkyl, or any of the pairs R₁₃ and R₁₄, or R₁₄ and R₁₅, or R₁₅ and R₁₆ or R₁₆ and R₁₇ may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring, or a pharmaceutically acceptable salt thereof.
 7. A compound according to claim 1 wherein: R₁ is:

wherein: R₁₈, R₁₉, R₂₀, R₂₁ and R₂₂ are the same or different and each represents hydrogen, halogen, hydroxy, optionally substituted amino, optionally substituted acyl, nitrile, optionally substituted C₁₋₃alkyl or optionally substituted alkoxy; and R₂₃ and R₂₄ are the same or different and each represents hydrogen, hydroxy, or optionally substituted C₁₋₃ alkyl, or a pharmaceutically acceptable salt thereof.
 8. A compound according to claim 1 of Formula (VIII):

wherein: R₂ is selected from the group consisting of NR₆R₇, substituted imidazole, substituted pyrazole, substituted pyrrole, substituted oxazole, substituted oxadiazole, substituted thiazole, substituted thiadiazole, substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted triazine, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, aminophenyl, acetamidophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzoxadiazole, substituted benzodioxole, substituted indoline, substituted indole, substituted indazole, and substituted benzomorpholine; and R₃ is H, F or CH₃; wherein: when X₁ is O, then R₄ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, substituted benzyl, substituted phenethyl, 3-phenylpropyl, methylpyridine, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide; and when X₁ is N, then R₄ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, substituted benzyl, substituted phenethyl, 3-phenylpropyl, methylpyridine, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide; or R₄ is taken together with X₁ and R₅ to form an optionally substituted saturated or partially saturated 5-7 membered ring with the general formula (II), or a pharmaceutically acceptable salt thereof.
 9. A compound as claimed in claim 8 wherein the 5-7 membered ring with the general formula (II) is selected from the group consisting of substituted piperidine, substituted morpholine, substituted piperazine, substituted pyrrolidine, and substituted imidazolidin-2-one, or a pharmaceutically acceptable salt thereof.
 10. A compound according to claim 1 of Formula (IX):

wherein: X₁ is selected from the group consisting of O and N; R₂ is NR₆R₇, substituted imidazole, substituted pyrazole, or substituted pyridine, phenyl, fluorophenyl, cyanophenyl, substituted tetrahydrobenzofuran, substituted benzopyran, substituted dihydrobenzodioxin, substituted benzoxazinone, substituted benzooxadiazole, substituted benzodioxole, substituted indoline, or substituted benzomorpholine; R₃ is H or F; R₆ and R₇ are methyl; and R₁₉, R₂₀ and R₂₁ are the same or different and each represents H, Cl, F, or CH₃, or a pharmaceutically acceptable salt thereof.
 11. A compound according to claim 1 selected from the group consisting of: N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-acetamide; 3-Methyl-3H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide; 1-Methyl-1H-imidazole-4-carboxylic acid [3-(benzenesulfonyl-benzyl-amino)-phenyl]-amide; N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-phenyl-acetamide; N-[3-(Benzenesulfonyl-benzyl-amino)-phenyl]-2-methoxy-acetamide; 1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide; N-Benzyl-N-[3-(3-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide; N-Benzyl-N-[3-(4-phenyl-piperazin-1-yl)-phenyl]-benzenesulfonamide; N-Benzyl-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide; Pyridine-3-sulfonic acid benzyl-[3-(4-phenyl-piperazin-1-yl)-phenyl]-amide; 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1,2-Dimethyl-1H-imidazole-4-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide; N-Benzyl-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide; N-Benzyl-3-cyano-N-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzenesulfonamide; N-Benzyl-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide; 1-Methyl-1H-pyrazole-4-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1,2-Dimethyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; N-(4-Chloro-benzyl)-3-cyano-N-(3-morpholin-4-yl-phenyl)-benzenesulfonamide; 2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; Pyridine-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[4-fluoro-3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[3-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-morpholin-4-yl-phenyl)-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-(3-morpholin-4-yl-phenyl)-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide; N-Benzyl-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide; 2-Methyl-2H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrazole-4-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide; N-(4-Chloro-benzyl)-3-cyano-4-fluoro-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide; N-(4-Chloro-benzyl)-N-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-benzenesulfonamide; Pyridine-3-sulfonic acid benzyl-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-(2-oxo-imidazolidin-1-yl)-phenyl]-amide; and Pyridine-3-sulfonic acid (4-chloro-benzyl)-[3-(2-oxo-imidazolidin-1-ylbenzyl)-[3-(2-oxo-imidazolidin-1-yl)-phenyl]-amide, or a pharmaceutically acceptable salt of any of the above.
 12. A pharmaceutical composition comprising at least one compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents and/or carriers.
 13. A compound as claimed in claim 8, wherein R₄ is methylpyridine, substituted hydroxyethyl, hydroxypropyl, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide, or a pharmaceutically acceptable salt thereof.
 14. A compound as claimed in claim 1, wherein R₃ is selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, and nitrile, or a pharmaceutically acceptable salt thereof. 